RESUMO
Cadmium (Cd) is a highly toxic metal that is distributed worldwide. Exposure to it is correlated with a vast number of diseases and organism malfunctions. Exopolysaccharides (EPS) derived from Lactiplantibacillus plantarum BGAN8, EPS-AN8, previously showed great potential for the in vitro protection of intestinal cells from this metal. Here, we investigated the potential of food supplemented with EPS-AN8 to protect rats from the hazardous effects of Cd exposure. After thirty days of exposure to lower (5 ppm) and higher (50 ppm)-Cd doses, the administration of EPS-AN8 led to decreased Cd content in the kidneys, liver, and blood compared to only Cd-treated groups, whereas the fecal Cd content was strongly enriched. In addition, EPS-AN8 reversed Cd-provoked effects on the most significant parameters of oxidative stress (MDA, CAT, GST, and GSH) and inflammation (IL-1ß, TNF-α, and IFN-γ) in the duodenum. Moreover, micrographs of the duodenum were in line with these findings. As the gut microbiota has an important role in maintaining homeostasis, we used 16S rRNA amplicon sequencing and investigated the effects of Cd and EPS-AN8 on one part of the microbiota presented in the duodenum. Although Cd decreased the growth of lactobacilli and mostly favored the blooming of opportunistic pathogen bacteria, parallel intake of EPS-AN8 reversed those changes. Therefore, our results imply that EPS-AN8 might be extremely noteworthy in combatting this toxic environmental pollutant.
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Cádmio , Suplementos Nutricionais , Ratos , Animais , Cádmio/toxicidade , RNA Ribossômico 16S/genética , Estresse Oxidativo , LactobacillusRESUMO
Skin can acquire cadmium (Cd) by oral route, but there is paucity of data concerning cutaneous effects of this metal. Cd acquired by oral route can affect skin wound healing, but the effect of Cd on other activities involved in skin homeostasis, including skin immunity, are not explored. Using the rat model of 30-day oral administration of Cd (5â¯ppm and 50â¯ppm) in drinking water, basic aspects of immune-relevant activity of epidermal cells were examined. Dose-dependent Cd deposition in the the skin was observed (0.035⯱â¯0.02⯵g/g and 0.127⯱â¯0.04⯵g/g at 5â¯ppm and 50â¯ppm, respectively, compared to 0.012⯱â¯0.009⯵g/g at 0â¯ppm of Cd). This resulted in skin inflammation (oxidative stress at both Cd doses and dose-dependent structural changes in the skin and the presence/activation of innate immunity cells). At low Cd dose inflammatory response (nitric oxide and IL-1ß) was observed. Other inflammatory cytokines (IL-6 and TNF) response occurred at 50â¯ppm, which was increased further following skin sensitization with contact allergen dinitro-chlorobenzene (DNCB). Epidermal cells exposed to both Cd doses enhanced concanavalin A (ConA)-stimulated lymphocyte production of IL-17. This study showed for the first time the effect of the metal which gained access to the skin via gut on immune reactivity of epidermal cells. Presented data might be relevant for the link between dietary Cd and the risk of skin pathologies.
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Cádmio/administração & dosagem , Pele/efeitos dos fármacos , Administração Oral , Animais , Citocinas/imunologia , Imunidade Inata/efeitos dos fármacos , Masculino , Óxido Nítrico/imunologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Pele/imunologiaRESUMO
PURPOSE: The efficacy of topical dinitrochlorobenzene (DNCB) in the treatment of some skin dermatoses is based both on local and systemic effects. It is not known, however, whether it can be applied to patients receiving some other therapy associated with systemic immunomodulation. The aim of the present paper using a rat model was to examine whether oral warfarin (WF) intake, as shown by others and by us, had an immunomodulatory potential to interfere with effects of topical DNCB as systemic immunotherapy. MATERIALS AND METHODS: Rats received 3.5 mg/l of WF sodium in drinking water for 30 days and were thereafter skin-sensitized with 0.4% DNCB. Changes in the oxidative activity (myeloperoxidase/MPO, reduction of nitroblue tetrazolium/NBT and nitric oxide/NO production) as well as tumor necrosis factor (TNF) production by peripheral blood polymorphonuclear cells (PMN) were measured and compared with PMN from sensitized unexposed to WF rats. RESULTS: WF intake enhanced some aspects of PMN activity (intracellular MPO activity and unstimulated NO production) as well as their responsiveness to exogenous stimulation (NBT reduction and TNF production from sensitized animals). However, WF also decreased PMN responsiveness of NO production to stimulation. WF affected NO and TNF production solely by PMN, as no effect on these activities of peripheral blood mononuclear cells was seen. CONCLUSION: Having in mind that polymorphonuclear leukocytes are the most abundant cell type in peripheral blood in humans, increase of basic aspects of PMN activity described in the present paper might be relevant for consideration of using WF as therapeutic modality in patients topically treated with DNCB.
Assuntos
Anticoagulantes/farmacologia , Dinitroclorobenzeno , Haptenos , Neutrófilos/efeitos dos fármacos , Varfarina/farmacologia , Administração Oral , Administração Tópica , Animais , Imunomodulação/efeitos dos fármacos , Interleucina-6/sangue , Contagem de Leucócitos , Masculino , Neutrófilos/metabolismo , Óxido Nítrico/metabolismo , Tempo de Tromboplastina Parcial , Peroxidase/metabolismo , Tempo de Protrombina , Ratos , Explosão Respiratória , Fator de Necrose Tumoral alfa/sangueRESUMO
PURPOSE: Warfarin (WF) is an anticoagulant which also affects physiological processes other than hemostasis. Our previous investigations showed the effect of WF which gained access to the organism via skin on resting peripheral blood granulocytes. Based on these data, the aim of the present study was to examine whether WF could modulate the inflammatory processes as well. To this aim the effect of WF on the inflammatory response induced by subcutaneous sponge implantation in rats was examined. MATERIALS AND METHODS: Warfarin-soaked polyvinyl sponges (WF-sponges) were implanted subcutaneously and cell infiltration into sponges, the levels of nitric oxide (NO) and inflammatory cytokines tumor necrosis factor (TNF) and interleukin-6 (IL-6) production by sponge cells were measured as parameters of inflammation. T cell infiltration and cytokine interferon-γ (IFN-γ), interleukin-17 (IL-17) and interleukin-10 (IL-10) were measured at day 7 post implantation. RESULTS: Warfarin exerted both stimulatory and suppressive effects depending on the parameter examined. Flow cytometry of cells recovered from sponges showed higher numbers of granulocytes (HIS48+ cells) at days 1 and 3 post implantation and CD11b+ cells at day 1 compared to control sponges. Cells from WF-sponges had an increased NO production (Griess reaction) at days 1 and 7. In contrast, lower levels of TNF (measured by ELISA) production by cells recovered from WF-soaked sponges were found in the early (day one) phase of reaction with unchanged levels at other time points. While IL-6 production by cells recovered from WF-soaked sponges was decreased at day 1, it was increased at day 7. Higher T cell numbers were noted in WF sponges at day 7 post implantation, and recovered cells produced more IFN-γ and IL-17, while IL-10 production remained unchanged. CONCLUSIONS: Warfarin affects some of the parameters of inflammatory reaction induced by subcutaneous polyvinyl sponge implantation. Differential (both stimulatory as well as inhibitory) effects of WF on inflammatory response to sponge implants might affect the course and/or duration of this reaction.
Assuntos
Inflamação/imunologia , Polivinil/administração & dosagem , Varfarina/administração & dosagem , Animais , Anticoagulantes/administração & dosagem , Anticoagulantes/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Citocinas/imunologia , Inflamação/metabolismo , Contagem de Leucócitos , Masculino , Óxido Nítrico/metabolismo , Peroxidase/metabolismo , Polivinil/farmacologia , Ratos , Pele/efeitos dos fármacos , Pele/imunologia , Pele/metabolismo , Varfarina/farmacologiaRESUMO
CONTEXT: Skin is the target of both acute and chronic exposure to warfarin, coumarin anticoagulant. Single exposure of rat skin to this agent induces early (24 h following epicutaneous administration) local response which might be part of inflammatory/reparatory homeostatic program or introduction to pathological events in exposed skin. OBJECTIVE: To examine time-dependent changes in skin of rats exposed to epicutaneously applied warfarin. MATERIALS AND METHODS: The effect of low (10 µg) and high (100 µg) doses of warfarin on histologically evident changes of epidermis (epidermal thickness) and dermis (numbers of mesenchymal cells and dermal capillaries), skin cell proliferative activity (Ki67(+) and PCNA(+) cells) and apoptotic (TUNEL(+)) and necrotic (ultra structural appearance) cells was examined one, three and seven days after the application. RESULTS: Both warfarin doses affected the majority of skin cell activity, but with differential time-course of skin epidermal and dermal cells state/activity. The occurrence of necrotic/apoptotic epidermal and dermal cells was noted the first day after the application and the activities which point to tissue reparation/remodeling were observed seven days after skin exposure to this agent. DISCUSSION: The observed pattern of changes (early evidence of cell/tissue injury which was later followed by signs of cell activity characteristic for tissue reparation/remodeling) implied warfarin-induced toxicity in skin cells as stimulus for subsequent activities relevant for tissue homeostasis. CONCLUSION: The data presented provide new and additional information concerning skin responses to warfarin that gains access to this tissue.
Assuntos
Anticoagulantes/toxicidade , Rodenticidas/toxicidade , Pele/efeitos dos fármacos , Varfarina/toxicidade , Administração Cutânea , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Antígeno Ki-67/metabolismo , Masculino , Necrose/induzido quimicamente , Necrose/patologia , Antígeno Nuclear de Célula em Proliferação/metabolismo , Ratos , Pele/metabolismo , Pele/patologia , Pele/ultraestruturaRESUMO
CONTEXT: Dermal toxicity of coumarin anticoagulant rodenticides, such as warfarin, represents potential risk for workers handling these agents and for individuals applying easily available rodenticides in their households as well. OBJECTIVE: In this study, proinflammatory effects of repeated epicutaneous administration of warfarin in rats were explored by examining inflammatory cytokine skin responses. MATERIALS AND METHODS: Ex vivo production of IL-1ß, IL-6, TNF-α and IL-17 by skin explants and by epidermal cells isolated by enzyme (dispase/trypsin) digestion from skin repeatedly (once a day, three consecutive days) exposed to 10 µg of warfarin was measured 24 h and 72 h following the last warfarin application by ELISAs for respective rat cytokines. RESULTS: Warfarin treatment resulted in histological changes, but skin or epidermal cell viability were not compromised, judging by MTT reduction assay. Both skin and epidermal cells responded to administration of this agent by production of all examined inflammatory cytokines (skin explants by TNF-α and IL-17; epidermal cells by IL-1ß and TNF-α) except IL-6. DISCUSSION: Along with histomorphological changes, cytokines indicate functional consequences in treated skin. IL-1ß production, that precede production of TNF-α, might be responsible for production of the latter cytokine. Sustained production of IL-1ß suggests persistence of epidermal cell stimulation or existence of some amplification mechanisms. Requirements for T cells seem to exist concerning epidermal cell IL-17 production. CONCLUSION: Presented data provide additional new information concerning proinflammatory effects of warfarin.
Assuntos
Anticoagulantes/farmacologia , Citocinas/biossíntese , Mediadores da Inflamação/metabolismo , Rodenticidas/farmacologia , Pele/efeitos dos fármacos , Animais , Masculino , Ratos , Pele/citologia , Pele/metabolismoRESUMO
OBJECTIVE: To evaluate immunologic mechanisms underlying Aspergillus fumigatus pulmonary infections in immunocompetent Dark Agouti (DA) and Albino Oxford (AO) rats recognized as being susceptible to some inflammatory diseases in different manners. METHODS: Lung fungal burden (quantitative colony forming units, CFU, assay), leukocyte infiltration (histology, cell composition) and their function (phagocytosis, oxidative activity, CD11b adhesion molecule expression) and cytokine interferon-γ (IFN-γ) and interleukin-17 and -4 (IL-17 and IL-4) lung content were evaluated following infection (intratracheally, 1x10(7) conidia). RESULTS: Slower reduction of fungal burden was observed in AO rats in comparison with that in DA rats, which was coincided with less intense histologically evident lung cell infiltration and leukocyte recovery as well as lower level of most of the their activities including intracellular myeloperoxidase activity, the capacity of nitroblue tetrazolium salt reduction and CD11b adhesion molecule expression (except for phagocytosis of conidia) in these rats. Differential patterns of changes in proinflammatory cytokine levels (unchanged levels of IFN-γ and transient increase of IL-17 in AO rats vs continuous increase of both cytokines in DA rats) and unchanged levels of IL-4 were observed. CONCLUSION: Genetically-based differences in the pattern of antifungal lung leukocyte activities and cytokine milieu, associated with differential efficiency of fungal elimination might be useful in the future use of rat models in studies of pulmonary aspergillosis.
Assuntos
Aspergillus fumigatus/imunologia , Pulmão/imunologia , Aspergilose Pulmonar/imunologia , Animais , Citocinas/metabolismo , Pulmão/metabolismo , Pulmão/microbiologia , Pulmão/patologia , Masculino , RatosRESUMO
The use of anticoagulant rodenticides (ARs) is one of the most commonly employed management methods for pest rodents. ARs compete with vitamin K (VK) required for the synthesis of blood clotting factors in the liver, resulting in inhibition of blood coagulation and often animal death due to hemorrhage. Besides rodents (target species), ARs may affect non-target animal species and humans. Out of hemostasis disturbance, the effects of ARs may be related to the inhibition of proteins that require VK for their synthesis but are not involved in the coagulation process, to their direct cytotoxicity, and their pro-oxidant/proinflammatory activity. A survey of the cellular and molecular mechanisms of these sublethal/asymptomatic AR effects is given in this review. Data from field, clinical, and experimental studies are presented. Knowledge of these mechanisms might improve hazard characterization and identification of potential ecotoxicological risks associated with ARs, contributing to a safer use of these chemicals.
Assuntos
Anticoagulantes , Rodenticidas , Animais , Humanos , Anticoagulantes/farmacologia , Rodenticidas/toxicidade , Coagulação Sanguínea , Ecotoxicologia , Fígado/metabolismoRESUMO
Acute respiratory distress syndrome (ARDS) became a focus of intensive research due to its death toll during the Covid-19 pandemic. An uncontrolled and excessive inflammatory response mediated by proinflammatory molecules such as high mobility group box protein 1 (HMGB1), IL-6, and TNF mounts as a response to infection. In this study, ethyl pyruvate (EP), a known inhibitor of HMGB1, was tested in the model of murine ARDS induced in C57BL/6 mice by intranasal administration of polyinosinic:polycytidylic acid (poly(I:C)). Intraperitoneal administration of EP ameliorated the ARDS-related histopathological changes in the lungs of poly(I:C)-induced ARDS and decreased numbers of immune cells in the lungs, broncho-alveolar lavage fluid and draining lymph nodes (DLN). Specifically, fewer CD8+ T cells and less activated CD4+ T cells were observed in DLN. Consequently, the lungs of EP-treated animals had fewer damage-inflicting CD8+ cells and macrophages. Additionally, the expression and production of proinflammatory cytokines, IL-17, IFN-γ and IL-6 were downregulated in the lungs. The expression of chemokine CCL5 which recruits immune cells into the lungs was also reduced. Finally, EP downregulated the expression of HMGB1 in the lungs. Our results imply that EP should be further evaluated as a potential candidate for ARDS therapy.
Assuntos
Proteína HMGB1 , Piruvatos , Síndrome do Desconforto Respiratório , Humanos , Animais , Camundongos , Linfócitos T CD8-Positivos/metabolismo , Proteína HMGB1/metabolismo , Interleucina-6 , Pandemias , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Síndrome do Desconforto Respiratório/tratamento farmacológicoRESUMO
The importance of issues associated with urban/commensal rats and mice (property damage, management costs, and health risks) press upon research on these animals. While the demography of commensal rodents is mostly studied, the need for understanding factors influencing their natural morbidity/mortality is also stressed. In this respect, more attention is expected to be paid to immunity, the physiological mechanism of defense against host survival threats (pathogens, parasites, diseases). Commensal rats and mice carry numerous pathogens that evoke diverse immune responses. The state of immunity in commensal house mice is studied in great detail, owing to the use of laboratory strains in biomedical research. Because commensal rats are, compared to mice, carriers of more zoonotic agents, rats' immunity is studied mainly in that context. Some of these zoonotic agents cause chronic, asymptomatic infections, which justified studies of immunological mechanisms of pathogen tolerance versus clearance regulation in rats. Occurrence of some infections in specific tissues/organs pressed upon analysis of local/regional immune responses and/or immunopathology. A survey of immunological activity/responses in commensal rats is given in this review, with mention of existing data in commensal mice. It should throw some light on the factors relevant to their morbidity and lifespan, supplementing the knowledge of commensal rodent ecology.
RESUMO
Since the realization that the lungs are not sterile but are normally inhabited by various bacterial species, studies have been conducted to define healthy lung microbiota and to investigate whether it changes during lung diseases, infections, and inflammation. Using next-generation sequencing, we investigated bacterial microbiota from whole lungs in two rat strains (previously shown to differ in gut microbiota composition) in a healthy state and during pulmonary infection caused by the opportunistic fungus Aspergillus fumigatus. No differences in alpha diversity indices and microbial composition between DA and AO rats before infection were noted. Fungal infection caused dysbiosis in both rat strains, characterized by increased alpha diversity indices and unchanged beta diversity. The relative abundance of genera and species was increased in DA but decreased in AO rats during infection. Changes in lung microbiota coincided with inflammation (in both rat strains) and oxidative stress (in DA rats). Disparate response of lung microbiota in DA and AO rats to pulmonary fungal infection might render these two rat strains differentially susceptible to a subsequent inflammatory insult.
Assuntos
Microbiota , Pneumonia , Ratos , Animais , Aspergillus fumigatus , Pulmão/microbiologia , InflamaçãoRESUMO
While the effect of gut microbiota and/or inflammation on a distant body site, including the lungs (gut-lung axis), has been well characterized, data about the influence of lung microbiota and lung inflammation on gut homeostasis (lung-gut axis) are scarce. Using a well-characterized model of pulmonary infection with the fungus Aspergillus fumigatus, we investigated alterations in the lung and gut microbiota by next-generation sequencing of the V3-V4 regions of total bacterial DNA. Pulmonary inflammation due to the fungus A. fumigatus caused bacterial dysbiosis in both lungs and gut, but with different characteristics. While increased alpha diversity and unchanged bacterial composition were noted in the lungs, dysbiosis in the gut was characterized by decreased alpha diversity indices and modified bacterial composition. The altered homeostasis in the lungs allows the immigration of new bacterial species of which 41.8% were found in the feces, indicating that some degree of bacterial migration from the gut to the lungs occurs. On the contrary, the dysbiosis occurring in the gut during pulmonary infection was a consequence of the local activity of the immune system. In addition, the alteration of gut microbiota in response to pulmonary infection depends on the bacterial composition before infection, as no changes in gut bacterial microbiota were detected in a rat strain with diverse gut bacteria. The data presented support the existence of the lung-gut axis and provide additional insight into this mechanism. IMPORTANCE Data regarding the impact of lung inflammation and lung microbiota on GIT are scarce, and the mechanisms of this interaction are still unknown. Using a well-characterized model of pulmonary infection caused by the opportunistic fungus Aspergillus fumigatus, we observed bacterial dysbiosis in both the lungs and gut that supports the existence of the lung-gut axis.
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The aim of this work is in situ anodization/anaphoretic deposition of a nano amorphous calcium phosphate (ACP)/chitosan oligosaccharide lactate (ChOL) multifunctional hybrid coating decorated with selenium (Se) on a titanium substrate and in vivo investigation of its immunomodulatory and anti-inflammatory effect. Investigating phenomena at the implant-tissue interface of interest for controlled inflammation and immunomodulation was also the aim of the research. In our earlier research, we designed coatings based on ACP and ChOL on titanium with anticorrosive, antibacterial and biocompatible properties, while in the presented results we show that selenium addition makes this coating an immunomodulator. The immunomodulatory effect of the novel hybrid coating is characterized by the examination of the functional aspects in the tissue around the implant (in vivo): proinflammatory cytokines' gene expression, M1 (iNOS) and M2 (Arg1) macrophages, fibrous capsule formation (TGF-ß) and vascularization (VEGF). The EDS, FTIR and XRD analyses prove the formation of a ACP/ChOL/Se multifunctional hybrid coating on Ti and the presence of Se. A higher M2/M1 macrophage ratio in the ACP/ChOL/Se-coated implants compared to pure titanium implants (a higher level of Arg1 expression) is noted at all time points examined (after 7, 14 and 28 days). Lower inflammation measured by gene expression of proinflammatory cytokines IL-1ß and TNF, lower expression of TGF-ß in the surrounding tissue and higher IL-6 expression (solely at day 7 post-implantation) is noted in presence of the ACP/ChOL/Se-coated implants.
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We recently demonstrated that macrophage migration inhibitory factor deficient (MIF (- / -)) mice exhibited a higher susceptibility to lethal systemic Aspergillus fumigatus infections than genetically matched, wild-type (WT) C57BL/6 mice, and displayed altered cytokine profiles in the spleen when challenged by sublethal infections. In this report we focused on the potential involvement of MIF in the response of mice to sublethal systemic A. fumigatus infections in tissues other than spleen. Impaired fungal clearance from lungs, kidneys, liver and brain in MIF (- / -) mice was noted and was associated with histologically-evident differences in signs of inflammation in these organs. Higher values of some indicators of pathologic changes in urine parameters (increases in bilirubin, glucose and ketones), as well as a greater degree of brain tissue damage, pointed to multiple organs being affected in MIF (- / -) mice. Analysis of the lung response revealed differences in the composition of infiltrated cells between MIF-sufficient and MIF-deficient mice. MPO activity and reactive oxygen species production were impaired, as well as production of IL-17 and IFN-γ in MIF (- / -) mice as compared to WT counterparts. Lower systemic IL-1ß and IL-6 levels in infected MIF (- / -) mice coincided with reduced blood neutrophil counts and organ infiltration. Collectively, this study identifies MIF as a resistance factor that orchestrates events in several non-lymphoid areas which provide a milieu that accomplishes anti-fungal A. fumigatus defense.
Assuntos
Aspergilose/microbiologia , Aspergilose/patologia , Aspergillus fumigatus/patogenicidade , Oxirredutases Intramoleculares/metabolismo , Pulmão/imunologia , Fatores Inibidores da Migração de Macrófagos/metabolismo , Animais , Aspergilose/imunologia , Aspergillus fumigatus/isolamento & purificação , Encéfalo/imunologia , Encéfalo/patologia , Contagem de Colônia Microbiana , Citocinas/metabolismo , Inflamação , Oxirredutases Intramoleculares/deficiência , Oxirredutases Intramoleculares/genética , Rim/imunologia , Rim/patologia , Fígado/imunologia , Fígado/patologia , Pulmão/patologia , Fatores Inibidores da Migração de Macrófagos/deficiência , Fatores Inibidores da Migração de Macrófagos/genética , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Contact hypersensitivity reaction (CHS) is a T-cell-mediated skin inflammatory reaction to cutaneous exposure to small sensitizing chemicals, haptens. While the significance of local inflammatory skin response to the hapten application in CHS induction and expression is known, there is paucity of data concerning systemic inflammation in CHS. In this study, changes in cellular (peripheral blood granulocytes) and humoral (plasma tumor necrosis factor (TNF)-α levels) components of inflammation during sensitization of rats with two consecutive applications of dinitrochlorobenzene (DNCB) were examined. The impact of sensitization on these parameters was determined by employing low (0.4%) and high (4%) hapten doses and by examining the dynamics (i.e. one and three days following the last application of DNCB) of these changes. Dose-dependent increase in relative numbers and priming (for respiratory burst and adhesion) effect of skin sensitization with DNCB on peripheral blood neutrophils in rats were noted. No changes in circulating TNF-α levels were observed following the sensitization. The increase in lung myeloperoxidase content and histologically evident presence of neutrophils was observed in lungs of the sensitized rats. The changes in granulocyte priming for adhesion might have accounted for the observed increase in lung neutrophil content in the sensitized rats.
Assuntos
Dermatite Alérgica de Contato/imunologia , Dinitroclorobenzeno/toxicidade , Irritantes/toxicidade , Administração Cutânea , Animais , Dermatite Alérgica de Contato/etiologia , Dinitroclorobenzeno/administração & dosagem , Granulócitos/efeitos dos fármacos , Granulócitos/imunologia , Irritantes/administração & dosagem , Contagem de Leucócitos , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Masculino , Peroxidase/imunologia , Ratos , Fator de Necrose Tumoral alfa/sangueRESUMO
Objective: The effect of oral cadmium (Cd) intake to influence contact skin allergies was examined, since it is known that Cd is a heavy metal that affects many tissues, including the skin, in which it disturbs homeostasis, thus resulting in inflammation and injury. Methods: Male rats were evoked with experimental contact hypersensitivity reaction (CHS) to hapten dinitrochlorobenzene (DNCB), after prolonged (30 day) oral exposure to an environmentally relevant Cd dose (5 ppm). The ear cell population was analyzed with flow cytometry. Cytokine production by ear skin cells and the activity of skin-draining lymph node (DLN) cells were measured using enzyme-linked immunosorbent assay (ELISA). Results: Orally acquired Cd (5 ppm) increased CHS intensity only in Dark Agouti (DA) rats by affecting inflammatory responses in both the sensitization (an increase of IFN-γ and IL-17 cytokine production) and challenge (an increase of CD8 + and CD4 + cell number and TNF, IFN-γ and IL-17 cytokine production) phases. An increased CHS reaction was seen in Albino Oxford (AO) rats only at a high Cd dose (50 ppm), during the challenge phase (an increase of CD8 + and CD4 + cell number and TNF, IFN-γ and IL-17 cytokine production). Conclusion: These novel data indicate that oral Cd intensifies the skin response to sensitizing chemicals such as DNCB.
Assuntos
Alérgenos , Cádmio , Masculino , Ratos , Animais , Alérgenos/toxicidade , Cádmio/toxicidade , Dinitroclorobenzeno/toxicidade , Interleucina-17 , CitocinasRESUMO
OBJECTIVE: To evaluate the effects of epicutaneous application of anticoagulant warfarin, by examining the presence of tissue injury and immune/inflammatory activity in exposed skin. METHODS: Rats were exposed to warfarin by applying 10 µg of warfarin-sodium to 10-12 cm(2) skin (range 0.8-1 µg per 1 cm(2)) for 3 consecutive days. Tissue injury was evaluated by lipid peroxidation, histomorphological changes and signs of reparative activity in skin. T cell infiltration and selected aspects of epidermal cell activity were examined as indicators of immune/inflammatory skin response to warfarin application. RESULTS: Repeated warfarin application exerted no effect on skin metabolic viability, but resulted in tissue injury (increased malondialdehyde, MDA, production, evident histo-morphological changes in epidermis and dermis depicting cell injury and death). Increased numbers of proliferating cell nuclear antigen (PCNA(+)) cells indicated reparative processes in injured skin. Infiltration of CD3(+) cells (T lymphocytes) along with the increased production of tumor necrosis factor-a (TNF-a) by epidermal cells from warfarin-treated skin and their co-stimulatory effect in an in vitro T-cell activation assay demonstrated immunomodulatory effects of epicutaneous warfarin. CONCLUSION: Presented data have documented tissue damage associated with immune/inflammatory activity in skin exposed to warfarin. Observed effects are relevant to immunotoxic potential of this anticoagulant in settings of external exposure.
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Dermatite de Contato/patologia , Rodenticidas/farmacologia , Varfarina/farmacologia , Animais , Complexo CD3/genética , Complexo CD3/metabolismo , Células Epidérmicas , Regulação da Expressão Gênica/fisiologia , Inflamação/metabolismo , Peroxidação de Lipídeos , Masculino , Antígeno Nuclear de Célula em Proliferação/genética , Antígeno Nuclear de Célula em Proliferação/metabolismo , Ratos , Pele/citologia , Pele/efeitos dos fármacos , Pele/metabolismo , Linfócitos T/fisiologiaRESUMO
OBJECTIVE: To investigate involvement of the aryl hydrocarbon receptor (AhR) in the immunomodulatory effects of cadmium (Cd). METHODS: The effect of Cd on AhR activation ( CYP1A1 and CYP1B1 mRNA expression) was examined in lung leukocytes of Cd-exposed rats (5 and 50 mg/L, 30 d orally) and by in vitro leukocyte exposure. The involvement of AhR signaling in the effects of Cd on the interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF) lung leukocyte response was investigated in vitro using the receptor antagonist CH-223191. RESULTS: Cd increased CYP1B1 ( in vivo and in vitro) and CYP1A1 ( in vitro) mRNA, indicating AhR involvement in the action of Cd. In response to Cd, lung leukocytes increased IL-6 and decreased TNF at the gene expression and protein levels, but decreased IL-1ß production due to reduced NLRP3. The AhR antagonist CH-223191 abrogated the observed effects of Cd on the cytokine response. The absence of AhR reactivity and cytokine response to Cd of leukocytes from the lungs of a rat strain that is less sensitive to Cd toxicity coincided with a high AhR repressor mRNA level. CONCLUSION: AhR signaling is involved in the lung leukocyte proinflammatory cytokine response to Cd. The relevance of the AhR to the cytokine response to Cd provides new insight into the mechanisms of Cd immunotoxicity.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Cádmio/toxicidade , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1B1/genética , Citocinas/imunologia , Poluentes Ambientais/toxicidade , Receptores de Hidrocarboneto Arílico/genética , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/imunologia , Citocromo P-450 CYP1A1/imunologia , Citocromo P-450 CYP1B1/imunologia , Masculino , Ratos , Receptores de Hidrocarboneto Arílico/imunologiaRESUMO
Cadmium (Cd) is a toxic heavy metal that when absorbed into the body causes nephrotoxicity and effects in other tissues.Anatomical barrier tissues are tissues that prevent the entry of pathogens and include skin, mucus membranes and the immune system. The adverse effects of Cd-induced immune cell's activity are the most extensively studied in the kidneys and the liver. There are though fewer data relating the effect of this metal on the other tissues, particularly in those in which cells of the immune system form local circuits of tissue defense, maintaining immune-mediated homeostasis. In this work, data on the direct and indirect effects of Cd on anatomical barrier tissue of inner and outer body surfaces (the lungs, gut, reproductive organs, and skin) were summarized.
Assuntos
Cádmio/toxicidade , Homeostase/efeitos dos fármacos , Sistema Imunitário/efeitos dos fármacos , Imunidade Celular/efeitos dos fármacos , Animais , Intoxicação por Cádmio/imunologia , HumanosRESUMO
Cadmium (Cd) represents a unique hazard because of the long biological half-life in humans (20-30 years). This metal accumulates in organs causing a continuum of responses, with organ disease/failure as extreme outcome. Some of the cellular and molecular alterations in target tissues can be related to immune-modulating potential of Cd. This metal may cause adverse responses in which components of the immune system function as both mediators and effectors of Cd tissue toxicity, which, in combination with Cd-induced alterations in homeostatic reparative activities may contribute to tissue dysfunction. In this work, current knowledge concerning inflammatory/autoimmune disease manifestations found to be related with cadmium exposure are summarized. Along with epidemiological evidence, animal and in vitro data are presented, with focus on cellular and molecular immune mechanisms potentially relevant for the disease susceptibility, disease promotion, or facilitating development of pre-existing pathologies.